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Ajax, Resolvyx Pharmaceuticals
"Through our collaboration with Celtic Therapeutics, our core focus is to develop resolvins for the treatment of a broad range of ophthalmic diseases. The lead ophthalmic resolvin program has completed a Phase 2 trial in chronic dry eye syndrome and is advancing to Phase 3 studies. Resolvyx seeks strategic partnerships for its non-ophthalmic programs allowing us to focus on developing resolvins for eye diseases."
http://www.resolvyx.com/about-us/index.asp
A good organic chemist can synthesize their drug from Icosapent Ethyl or you can take Vascepa-ASA (enteric coated ASA) and stay away from COX-2 inhibitors.
I have a pain pilot study, N=1 fibromyalgia >10 yrs, Vascepa 2 grams Enteric ASA 162 mg BID...
Williams
JL, Thanks for looking into it, tons of research out there funded with NIH grants. It's also interesting to note a lot of the reasearch is coming from Brigham and Women's Hospital, they happen to own the two EPA patents related to the treatment of asthma. (Harvard Researchers)
The DHA products of this mechanism are: Protectins (Neuroprotectins) and Maresins...many of these look like great canidates for NDA post ischemic stroke.
Key Words:
18R series resolvins
Resolvin E1 and E2 (RvE1, RvE2)
All of these molecules vary slightly from the EPA molecule (esters bonds/-OH/+H), and perhapse the reason for lack of NCE decison:)
In my head the value of Amarins EPA (IP protection, EPA composition patents) just more than doubled.
Williams
Aumeoli,
Just curious as whether it (aspirin) could be helping your IBS symtoms when combined with Vascepa. A COX-2 inhibitor takes away from many of the "good" effects of Vascepa. It's unclear to me what effect aspirin may have with the production of resolvins. Do your IBS symptoms flare with Ibuprofen use?
Williams
Ajax, the understanding of this mechanism is new science. Specifically the Resolvins derived from EPA. The mechanism I'm describing are separate from a COX-1 inhibitor or a COX-2 heart attack Viox inhibitor.
"Aspirin exerts its actions by the inhibition of both COX-1 and COX-2 (cyclooxygenase 1 and 2) which has a direct negative effect on prostaglandin synthesis. It irreversibly acetylates COX-2 which loses the ability to generate prostaglandin intermediates. However, COX-2 retains oxygenase activity which results in the production of several types of anti-inflammatory mediators. This pathway describes the aspirin triggered conversion of : 5Z8Z11Z14Z17Z-EICOSAPENTAENOATE to anti-inflammatory mediators of the resolvin E1 and 2.. About this Pathway Aspirin mediated acetylation of COX-2 triggers the synthesis of resolvins E1 and E2 from eicosapentaenoate."
http://www.ncbi.nlm.nih.gov/biosystems/782386
Aspirin + COX-2 oxygenase activity + EPA = Resolivins E1 & E2
!!!!A COX-2 inhibitor like Viox would inhibit the above Aspirin sparing pathway.!!!!===
In a mice study, RvE1 was 1000 to 10,000 more potent than morpine or a commonly studied COX-2 inhibitor.
Both DHA and EPA make these resolvins, but DHA work's more at eye's, brain, and neural tissues.
EPA: RvE1 & RvE2
DHA: RvD1 & RvD2
=========================
Completely aside, many of the active molecules in these pathways have ester bonds that differentiate them. Several are being studied for CVD, Asthma, Infalmation diseases, and chronic pain.
All eye's are on Vascepa's NCE decision, a no would mean many of these Resolvins would be Vascepa's "bitch":)
JL,
Haven't read through all your posts...did you cover this? Because the combo of ASA and EPA is essentially a Resolvin drug, exerting inhibitory action on leukocyte transendothelial migration and IL-2 production. That's a BFD, right? Will
"Aspirin exerts its actions by the inhibition of both COX-1 and COX-2 (cyclooxygenase 1 and 2) which has a direct negative effect on prostaglandin synthesis. It irreversibly acetylates COX-2 which loses the ability to generate prostaglandin intermediates. However, COX-2 retains oxygenase activity which results in the production of several types of anti-inflammatory mediators. This pathway describes the aspirin triggered conversion of : 5Z8Z11Z14Z17Z-EICOSAPENTAENOATE to anti-inflammatory mediators of the resolvin E1 and 2.. About this Pathway Aspirin mediated acetylation of COX-2 triggers the synthesis of resolvins E1 and E2 from eicosapentaenoate. Resolvin E1 has been found to be 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoate . The enzyme 5-lipooxygenase is pivotal in the catalysis of 18-HEPE to 5S,18-HEPE which leads to the downstream production of resolvins E1 and E2 . Resolvin E1 has proven inhibitory action on leukocyte transendothelial migration and IL-2 production."
Do you take aspirin too? Thanks Will
This is new to me!!! "RESOLVINS" Amarin's R&D I hope is informed of this. (ASA + EPA treaments)
Resolvins are a recently discovered family of naturally-occurring, small molecule lipid mediators that can be targeted to treat a wide range of diseases. In particular, resolvins act to protect healthy tissue during an immuno-inflammatory response to infection, injury or other environmental challenge, and then act to resolve inflammation and promote healing after the environmental insult has passed. Resolvins have shown highly potent efficacy in pre-clinical models of asthma, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, dry eye and retinal disease, among others.
Resolvins are potential drug candidates to treat a broad range of acute and chronic diseases caused by a failure to resolve the inflammatory response and restore immune homeostasis. Such diseases include auto-immune diseases (like Crohn's disease, psoriasis and rheumatoid arthritis), allergic diseases (like asthma) and chronic inflammatory disease (like atherosclerosis, degenerative retinal diseases, chronic dry eye and Alzheimer's disease). Resolvins offer an entirely novel biological approach to treating significant inflammatory diseases, with a decreased potential for immuno-suppression.
About Resolvyx Pharmaceuticals
Resolvyx Pharmaceuticals is a privately-held biopharmaceutical company dedicated to the discovery, development and commercialization of resolvins, a novel class of therapies to treat inflammatory diseases and their complications. Resolvyx's drug R&D programs are focused on characterizing and developing resolvin-based compounds. With its experienced management team, world-class scientists and leading investors, Resolvyx is well-positioned to capitalize on its extensive portfolio of more than 55 patents and applications. The company's headquarters are in Bedford, Massachusetts.
http://www.drugs.com/clinical_trials/resolvyx-present-data-novel-resolvin-candidates-eye-arvo-annual-meeting-4068.html
JL, I found some very interesting research angles. Have you've heard of Resolvins?
http://en.wikipedia.org/wiki/Resolvins
The combination of ASA and EPA may hold SIGNIFICANT medical value for neumerous chronic diseases.(Asthma, IBS, Crohns, !Cancer!, and CVD)
http://www.ncbi.nlm.nih.gov/biosystems/782386
After reading the above, I think at this time it's impossible to put valuation on the company that owns the Composition Patents on concentrated EPA.
Williams
Claims progressively expand 13417899. Good stuff! Explains the rumors started Sunday night;).
AMR102 data could be delayed, at the last investor conference it wasn't highlight to be out in the first half as previously discussed. Another company could have requested a trial with a different statin, now that could be interesting.
A possibility that hasn't been discussed is a Royality AMR 102 agreement to finanace an Anchor launch.
We could see an interesting next 60 days..
We all make mistakes, even the smartest of Brain Surgeons and Rocket Scientists...I know both. This practitioner may grow to be the largest prescriber/promoter of Vascepa related to these events.
Yes, it was horrible to the point I wasn't going to comment...but I probable will.
Wm, as I understand the MECHANISMS of action's r/t Leukotrienes, Vascepa <could&should> reduce the use of rescue inhalators via reduction in pro-inflamatory leukotrienes. They're many studies r/t "fish oil" improving exercise induced asthma. Very interesting to hear your insight, I've noticed more endurance on the tread mill,,,,but put it off to placebo effects:) JL, any insight into the possible benefits r/t asthma/reactive airway diseases?
(ALWAYS CARRY YOUR ALBUTEROL EVEN THOUGH YOUR SYMPTOMS DECREASED)
Williams
16% growth is STRONG, we might be getting the effects of Tier 2 or 5+ visits per high prescribing MD.
I hope to get some clarity r/t NCE this week...not that it matters with the strong growth & IP. (A couple phone class & emails out)
I've been doing some IP/patent research lately, IMO Amarin wall is high, thick, and circular.
JL, I had an interesting conversation with a M.D./Ph.D Asthma researcher on Friday, any opinion on EPA and Leukotriene antagonist mechanisms.
Williams
Jim are saying you know nothing about the IP Pharmacon "owns" r/t Vascepa. 23 Listed or approved and 30 late stage EPA Patents covering EPA, EPA/Statin combos, EPA blood levels, EPA triglycerides, and EPA/ hydroxy-statin NCE possibilities.
All of Amarin's Patents are secured until debt is paid in full.
Duh, lol
OK found it, " Pharmakon's management team has a long and successful track record of structuring securitized financings and making direct investments in bio-pharmaceutical royalty interests. Pablo Legorreta, co-founder and Managing Member of Pharmakon, is also the founder and CEO of Royalty Pharma. Royalty Pharma is the industry leader in acquiring revenue-producing intellectual property, principally royalty interests in marketed and late stage biopharmaceutical products, with assets of over $7 billion. Pablo Legorreta commented: "Pharmakon's investment focus on debt secured by royalties, its three to five year target maturity and efficient structure, increases the availability and drives down the cost of much needed capital in the biotech industry."
Did Royality Pharma catch wind of an Amarin/Elan deal and not want their Pharmakon investment with Amarin spoiled?
Study
How is Royalty Pharma related to Pharmakon?
I must have missed something.
Williams
Anyone know when we got the 9858 volume for today's 7 calls?
Although the page says updated, for May the current Cumulative Supplement isn't posted yet.
Thanks
If I didn't confuse you enough yesterday there's a new spin, sorry.
It's possible this guidance posted after the April OB held up an Amarin decision:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM281764.pdf
This is both really really good for Vascepa and neutral for all the science crap yesterday.
First, the good news...for Amarin... EPA (whatever the structure will be considered EPA) under the ANDAs: Pharmaceutical Solid Polymorphism: Chemistry, Manufacturing, and Controls Information, July 2007. Again, this shoots AZN in the foot with Omthera's Epanova...it's generic. Neutral that the new science may not guide in the NCE decision. Dangerous for the shorts, all the information may be out for the decision, finally!
I'm starting to hate this NCE BS!
Will
YB, the "new" science wouldn't disagree with his statement.
"The active moiety in GlaxoSmithKline’s Lovaza, a similar agent for the treatment of hypertriglyceridemia, is a mixture of omega-3-acid ethyl esters that includes icosapent ethyl (EPA), docosahexaenoic acid (DHA), and a few others. Without requiring GlaxoSmithKline to specify which ester helps to lower triglycerides, the FDA considered the mixture of EPA and DHA as the active moiety that is responsible for the physiological and pharmacological action of Lovaza. Vascepa might have an advantage over Lovaza; it does not increase LDL-C levels, which has sometimes been observed with Lovaza.
The FDA considers Vascepa to be a new chemical entity. It contains only EPA but not DHA, and it does not contain any appended portions of both EPA and DHA that cause them to be an ester, salt, or other non-covalent derivative. Therefore, its active moiety has not been previously approved by the FDA in any other application submitted under Section 505(b) of the Federal Food, Drug, and Cosmetic Act."
He made no comment that the FDA considered Icosapent Ethyl, a prodrug...he may have not had access to the Medical Review document at the time of his statement. Also, it's likely he knew nothing of the 2D & 3D variation potential in the two EPA molecules. I suspect the EPA is a homogeneous mix of "cis EPA" in Vascepa, While Lovaza's mix is more heterogeneous with possible variances in EPA structure from different fish sources. (Just speculation though)
His statement is general and makes perfect sense, if the new science theory is correct, it makes perfect science and a crystal clear NCE decision.
Williams
Thanks
Phil, leave me your AMRN shares in your Will.
thanks
Will
No doubt we all want this over! NCE is a non issue with Amarin's IP. We'll be 1 yr next month, quite pathetic!
YoYo, this is confusing stuff.
Lovaza:
(5Z,8Z,11Z,14Z,17Z)-ethyl 5,8,11,14,17-eicosapentaenoate) "this is the Lovaza EPA source"
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=135261807
Read:
Stereoisomers:
In stereoisomers the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs. This class includes enantiomers where different isomers are non-superimposable mirror-images of each other, and diastereomers when they are not.
Diastereomerism is again subdivided into "cis–trans isomers", which have restricted rotation within the molecule (typically isomers containing a double bond) and "conformational isomers" (conformers), which can rotate about one or more single bonds within the molecule.
An obsolete term for "cis–trans isomerism" is "geometric isomers".[3]
For compounds with more than two substituents E-Z notation is used instead of cis and trans. If possible, E and Z (written in italic type) is also preferred in compounds with two substituents.[4]
Bla Bla........
While structural isomers typically have different chemical properties, stereoisomers behave identically in most chemical reactions, except in their reaction with other stereoisomers. Enzymes however can distinguish between different enantiomers of a compound, and organisms often prefer one isomer over the other. Some stereoisomers also differ in the way they rotate polarized light.
http://en.wikipedia.org/wiki/Isomer
So it's likely Vascepa and Lovaza EPA's experience Diastereomerism. (Vascepa cis)ethyl all-cis-5,8,11,14,17-icosapentaenoate and (Lovaza Z)5Z,8Z,11Z,14Z,17Z)-ethyl 5,8,11,14,17-eicosapentaenoate.
E & Z:
E-Z notation, or the E-Z convention, is the IUPAC preferred method of describing the stereochemistry of double bonds in organic chemistry. It is an extension of cis/trans notation that can be used to describe double bonds having three or four substituents.
Following a set of defined rules (Cahn-Ingold-Prelog priority rules), each substituent on a double bond is assigned a priority.
If the two groups of higher priority are on opposite sides of the double bond, the bond is assigned the configuration E (from entgegen, German: [?nt'ge?g?n], the German word for "opposite").
If the two groups of higher priority are on the same side of the double bond, the bond is assigned the configuration Z (from zusammen, German: [tsu'zam?n], the German word for "together").
Trans-2-butene.svg
http://en.wikipedia.org/wiki/E-Z_notation
===========
Laymans
Vascepa and Lovaza EPA sources are from two different molecules structurally & different efficacy at the same target receptors. Both have the same number of double bonds, same molecular formula and same weight weight. They are "shaped" chemically different.
Hope that helps.
Someone post to YB and stock twits...thanks
It's looks like Amarin might have the structure confused too:)
Vascepa label is listed as ethyl all-cis-5,8,11,14,17-icosapentaenoate or Icosapent Ethyl the active ingrediant in the OB.
http://www.vascepa.com/full-prescribing-information.pdf
Pub Chem search has ethyl all-cis-5,8,11,14,17-icosapentaenoate listed as:
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3298
This is NOT Icosapent Ethyl. Icosapent ethyl is:
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9831415
According to PubChem, an NIH site, Icosapent Ethyl is not ethyl all-cis-5,8,11,14,17-icosapentaenoate. Either Amarins label is wrong or the NIH is wrong.
It's likly the wild natural "fish oil" is one and Vascepa is the other considering the chemical treatment of fish oil to derive Vascepa.
Epadel is interestingly considered Icosapent Ethyl and likly has fueled some of the confusion.
Lovaza is considered to have "ICOSAPENT (EPA ETHYL ESTER",
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9831414
Confused yet?
Lovaza is likely contains EPA of "ICOSAPENT (EPA ETHYL ESTER" and Vascepa (the chemically altered isomer) ethyl all-cis-5,8,11,14,17-icosapentaenoate.
The two have the same molecular formula but chemically separate 2D and 3D structures. Epadel likely messed up and called it's drug Icosapent Ethyl and Amarin copied their homework. The correct name for both Epadel and Vascepa I suspect is "ethyl all-cis-5,8,11,14,17-icosapentaenoate" and should be corrected at the FDA website and label. Lovaza's Omega source should be listed as (4,7,10,13,16,19-Docosahexaenoic acid, ethyl ester, (4Z,7Z,10Z,13Z,16Z,19Z)-, mixt. with (5Z,8Z,11Z,14Z,17Z)-ethyl 5,8,11,14,17-eicosapentaenoate)
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=135261807
In conclusion, any way you skin it, Vascepa is a NCE...how do you like them apples shorty.
Williams
It unlikely the FDA will need to wait for anything (Lovaza Citizen Petition) the isomers are two separate chemicals:). Expect manipulation today as this appears to be new stuff.
Williams
For those institutions that are betting on a strict chemical interpretation of Lovaza's EPA and Vascepa EPA being the same, you might be very disappointed.
The EPA or Ethyl EPA in Vascepa is chemically derived from "fish oil". It is uniformally Icosapent Ethyl, cis-5,8,11,14,17-Eicosapentaenoic acid. As per the RDL it's "derived".
The EPA in Lovaza is the wild EPA ee, it has different stereo chemistry than the manufactured E-EPA. Lovaza likely has many Stereoisomers of EPA (53) known.
Two very different chemicals;)
All new info, to me r/t the number of EPA isomers.
Williams
How many Stereoisomers are there for E-EPA/Icosapent Ethyl?
53
http://en.m.wikipedia.org/wiki/Stereoisomerism
Stereoisomers can have different biological efficasys.
NCE Question #2
Which one is cis-5,8,11,14,17- Eicosapentaenoic acid ethyl ester?
AMR 101 or Vascepa?
http://www.ncbi.nlm.nih.gov/pcsubstance?cmd=search&term=%22ICOSAPENT+ETHYL%22%5BCompleteSynonym%5D+9831415%5Bstandardizedcid%5D
NCE chemistry test questions?
1) Which stereoisomers of EPA is Vascepa?
1,2,3,4,5,6
http://www.ncbi.nlm.nih.gov/pccompound?cmd=Link&LinkName=pccompound_pccompound_sameconnectivity_pulldown&from_uid=9831415
2) Is Vascepa different from Epadel (Japan's EPA)?
3) Anyone know the stereoisomers of Lovaza?
http://us.gsk.com/products/assets/us_lovaza.pdf
A pictures worth a Thousand words.
Williams
Unable to search Icosapent Ethyl in OB now @ 2:04 est. strange.
Not really how I would read it. I think there was miscommunication between the FDA from the get go. Ad Coms are generally for safety & efficasy reasons not exclusivity. The safety data for Anchor & Marine is similar to placebo. Efficasy for Anchor is clearly met with 4 GM dose, it met all endpoints of the SPA.
The FDA failed to communicate how it viewed Icosapent Ethyl and Amarin didn't ask the question until 6-20-12 meeting.
The citizen petition added a new twist to match Lovaza label to what listed in the OB. Lovaza's wasn't a reference listed drug until 9-2012.
Timing of Amarin's decision may be held until petition is answered, mid-August per the FDA.
As Amarin stated an Anchor Ad Com would be based on first Omega-3 for high Trigs, so it would likely focus on efficasy not NCE.
Whether or not Vascepa is a NCE is NOT clear. Has the Active Moiety in Vascepa ever been approved before?
Yes and No
Yes, Icosapent Ethyl coverts into EPA once metabolized by pancreatic Lipase, No Icosapent Ethyl is not listed in the OB nor was EPA listed in the RLD approval of Vascepa.
It's a call that could go either way, but all the movement of FDA, USP monograph and one year wait...points to NCE IMO.
It's just not likely to happen until after the citizen petition is answered.
"FDA Preliminary Response: Under 505(s) of the FD&C Act, all new chemical entities must either be discussed at an Advisory Committee Meeting or a justification provided as to why it will not be discussed. A final decision on whether AMR101 is a new chemical entity has not been made.
Meeting Discussion: The firm pressed for a more definitive response given the limited resources of the company. The sponsor was informed that, based on what is known about the compound at this time, and in our opinion it was less likely that AMR101 would go to an Advisory Committee. Final decision on the question of an Advisory Committee would be made after submission of the NDA"
----FUBAR----
Amarin should have had an Advisory Committee for Marine, the FDA did not understand the Omega 3 situation.
Likely the June 22, 2012 meeting save the miss branded 3 yr NME at PDUFA date.
New FDA Documents posted R/T NCE discussions, they are listed in the Review section under "administrative documents"
Reading now
Label is unchanged:
"These are predominantly a combination of ethyl
esters of eicosapentaenoic acid (EPA - a
pproximately 465 mg) and docosahexaenoic acid (DHA
-approximately 375 mg"
465+375=840mg "At Least"
something fishy going on
Williams
Thanks YB, I think it change too. As I read it I ask myself what the hell does the other 100MG contain...don't remember asking that question before.
After the millions of times I've looked at them you'd expect me to know. LOL
I don't remember the OB definition of Lovaza being so watered downed.
The OB: "1GM CONTAINS AT LEAST 900MG OF THE ETHYL ESTERS OF OMEGA-3 FATTY ACIDS"
"1GM contains 900MG"
"At Least"
It seems like it changed but I'm not 100% sure.
The OB today reads:
Active Ingredient: OMEGA-3-ACID ETHYL ESTERS CAPSULE; ORAL 1GM CONTAINS AT LEAST 900MG OF THE ETHYL ESTERS OF OMEGA-3 FATTY ACIDS LOVAZA SMITHKLINE BEECHAM
Active Ingredient: ICOSAPENT ETHYL CAPSULE; ORAL 1GM VASCEPA AMARIN PHARMA INC
I could not access the Lovaza earlier today, now it reads Lovaza 1 GM contains at least 900MG of the ethyl esters of omega-3 fatty acids.
YB, You are correct about the SPA. Agreement would only be changed for a major safety issue.